Dosage aerosols for the application of pharmaceutical formulations

ABSTRACT

The invention relates to pharmaceutical active substances, active substance mixtures and formulations for use as an aerosol in propellant-containing [1.1.1.2-tetrafluoroethane (HFC-134a) or 1.1.1.2.3.3.3-heptafluoropropane(HFC-227)] metered-dose aerosols and the metered-dose aerosols for administering these active substances, active substance mixtures and formulations.

This application claims priority of DE 10 2006 014 433, which application is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to pharmaceutical active substances, active substance mixtures and formulations for use as an aerosol in propellant-containing [1.1.1.2-tetrafluoroethane (HFC-134a) or 1.1.1.2.3.3.3-heptafluoropropane(HFC-227)] metered-dose aerosols and the metered-dose aerosols for administering these active substances, active substance mixtures and formulations.

2. Description of the Prior Art

The use of the delivery of aerosol formulations of medicaments by pressurised, dosage-measuring inhalers (MDIs, standing for “metered-dose inhalers”) is widespread in therapy, as in the treatment of asthma and diseases that cause obstruction of the airways. Compared with oral administration, inhalation results a faster onset of activity and at the same time reduces systemic side-effects to a minimum. Aerosol formulations can be administered by inhalation through the mouth or topically by application to the nasal mucosa.

Formulations for administering aerosol using MDIs may consist of solutions or suspensions. Solution formulations have the advantage over suspension formulations that the pharmaceutical compositions are fully dissolved in the propellant and thus have a homogeneous nature. Solution formulations also avoid the problems associated with suspension formulations of physical instability and thus ensure the administration of equal doses for a longer period. In addition, solution-type metered-dose aerosols generally do not require the addition of surfactants. Moreover, there are so-called “suslutions” as disclosed in US2004/0184994 for example.

The administration of aerosol solution formulations by MDIs is dependent on the propellant force of the propulsion system used to produce them.

Conventionally, the propellant contains a mixture of chlorofluorocarbons (CFCs) to guarantee the desired properties of solubility, vapour pressure and stability of the formulation. However, as it has been established in the mean time that CFCs are damaging to the environment because they contribute to the depletion of the earth's ozone layer, the environmentally harmful CFC propellant present in aerosol inhalation formulations is being replaced by environmentally acceptable partly fluorinated hydrocarbon propellants (HFC propellants) or other non-chlorinated propellants.

Although there are a great many metered-dose aerosols on the market, their metering accuracy is suitable for improvement.

SUMMARY OF THE INVENTION

The aim of the present invention is to provide a device with increased metering accuracy for the active substance, active substance mixture or formulation to prepare.

The above aim is achieved by a device according to claim 1. Advantageous further features are the subject of the subsidiary claims.

In a first aspect of the present invention, the mouthpiece tube of the device has a channel (8) which has no or almost no dead volume on its side remote from the metered-dose aerosol.

The term “dead volume” is defined as the space which projects beyond the nozzle bore (9) and thus does not lie in the direct flow path.

BRIEF DESCRIPTION OF THE DRAWINGS

Further advantages, features, properties and aspects of the present invention will become apparent from the following description of preferred embodiments with reference to the drawings, wherein:

FIG. 1: shows a mouthpiece tube with dead volume;

FIG. 2: shows a mouthpiece tube with reduced dead volume;

FIGS. 3 and 4: show a mouthpiece tube (the mouthpiece tube according to the invention in each case) with optimised reduction of the dead volume;

FIG. 5: shows a mouthpiece tube as in FIG. 1 a with reference numerals

The Figures designated “a” in each case show a longitudinal section in side view.

The Figures designated “b” in each case show a longitudinal section in plan view.

In the Figures the same reference numerals have been used for identical or similar parts having corresponding or comparable properties and advantages, even if the corresponding description is not repeated.

DETAILED DESCRIPTION OF THE INVENTION

The mouthpiece tube is a component with a number of functions:

The mouthpiece tube according to FIG. 5 functionally consists of a shaft (2), a valve stem receptacle (5), a nozzle bore (9) and the mouthpiece (6).

The mouthpiece tube accommodates the metered-dose aerosol such that the shaft (2) of the mouthpiece tube surrounds the metered-dose aerosol (1) and the valve stem receptacle (5) of the mouthpiece tube encloses the valve stem (4) of the metering valve (3) to form a seal.

The mouthpiece tube shaft (2) has the function of safely preventing canting of the valve stem (4) relative to the other valve components (3), which would be harmful to the valve (3), by restricting the room for movement of the metered-dose aerosol. In addition, the valve stem receptacle (5) forms an abutment that limits the depth of immersion of the valve stem (4) in the stem receptacle of the mouthpiece tube.

The valve stem receptacle has a channel (8) which the actual nozzle bore (9) impacts upon at an obtuse angle to its perpendicular axis. The nozzle bore has a diameter of 0.2-0.6 mm, preferably between 0.5-0.6 mm for suspension formulations and suslutions, as well as between 0.2-0.27 mm for solution formulations.

As a result, the active substance formulation which is liquefied under pressure can be deflected through >90° from the perpendicularly downwardly arranged opening of the valve stem (7) and pass outwards through the nozzle bore (9). The spray cloud is finally generated at the transition from the nozzle bore (9) to the nozzle opening (10).

The alteration to the mouthpiece tube described in the invention is achieved by a substantially more exact positioning of the tool part comprising the nozzle pin and the core of the valve stem receptacle to one another by a conventional injection moulding process.

Examples of dimensions of valve stems:

external diameter of internal diameter of the Valve/manufacturer the valve stem valve stem at the opening Bespak, BK357 3.17 ± 0.01 mm 2.12 ± 0.03 mm Valois, DF31/50RCU 3.19 ± 0.01 mm 1.48 ± 0.02 mm 3M, Neotechnic 2.76 ± 0.01 mm 1.68 ± 0.04 mm

In a second aspect of the present invention, the channel (8) is connected, via a nozzle bore (9), to a nozzle opening of funnel-shaped construction.

It is clear from the description that the device according to the invention is suitable for administering suitable active substance, or any suitable active substance mixture or formulation as single doses.

Examples of pharmaceutically effective active substances, active substance mixtures, or formulations (pharmaceutical preparation) include all the inhalable compounds, such as, e.g., inhalable macromolecules, as disclosed in EP 1 003 478. Preferably active substances, active substance mixtures or formulations for the treatment of respiratory complaints which are taken by inhalation are used.

The compounds listed below may be used in the device according to the invention on their own or in combination. In the compounds mentioned below, W is a pharmacologically active substance and is selected (for example) from among the betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, and PI3-kinase inhibitors. Moreover, double or triple combinations of W may be combined and used in the device according to the invention. Combinations of W might be, for example:

-   -   W denotes a betamimetic, combined with an anticholinergic,         corticosteroid, PDE4-inhibitor, EGFR-inhibitor or         LTD4-antagonist,     -   W denotes an anticholinergic, combined with a betamimetic,         corticosteroid, PDE4-inhibitor, EGFR-inhibitor or         LTD4-antagonist,     -   W denotes a corticosteroid, combined with a PDE4-inhibitor,         EGFR-inhibitor or LTD4-antagonist     -   W denotes a PDE4-inhibitor, combined with an EGFR-inhibitor or         LTD4-antagonist     -   W denotes an EGFR-inhibitor, combined with an LTD4-antagonist.

The compounds used as betamimetics are preferably compounds selected from among albuterol, arformoterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmefamol, salmeterol, soterenol, sulphonterol, terbutaline, tiaramide, tolubuterol, zinterol, CHF-1035, HOKU-81, KUL-1248, and

-   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide -   5-[2-(5.6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one -   4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl[sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone -   1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol -   1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol -   1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol -   5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one -   1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol -   6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one -   6-hydroxy-8-{1-hydroxy-2-[2-(ethyl     4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one -   6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic     acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one -   8-{2-[1,1-dimethyl-2-(2.4.6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one -   6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one -   6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one -   8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one -   8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one -   4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3.4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric     acid -   8-{2-[2-(3.4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one -   1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol -   2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-benzaldehyde -   N-[2-hydroxy-5-(1-hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}-ethyl)-phenyl]-formamide -   8-hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}-ethyl)-1H-quinolin-2-one -   8-hydroxy-5-[1-hydroxy-2-(6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one -   5-[2-(2-{4-[4-(2-amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one -   [3-[4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-5-methyl-phenyl]-urea -   4-(2-{6-[2-(2.6-dichloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol -   3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzylsulphonamide -   3-(3-{7-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-heptyloxy}-propyl)-benzylsulphonamide -   4-(2-{6-[4-(3-cyclopentanesulphonyl-phenyl)-butoxy]-hexylamino}-1-hydroxy-ethyl)-2-hydroxymethyl-phenol -   N-Adamantan-2-yl-2-(3-{2-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-propyl}-phenyl)-acetamide     optionally in the form of the racemates, enantiomers, diastereomers     thereof and optionally in the form of the pharmacologically     acceptable acid addition salts, solvates or hydrates thereof.     According to the invention the acid addition salts of the     betamimetics are preferably selected from among the hydrochloride,     hydrobromide, hydriodide, hydrosulphate, hydrophosphate,     hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,     hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,     hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulphonate.

The anticholinergics used are preferably compounds selected from among the tiotropium salts, preferably the bromide salt, oxitropium salts, preferably the bromide salt, flutropium salts, preferably the bromide salt, ipratropium salts, preferably the bromide salt, glycopyrronium salts, preferably the bromide salt, trospium salts, preferably the chloride salt, tolterodine. In the above-mentioned salts the cations are the pharmacologically active constituents. As anions the above-mentioned salts may preferably contain the chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts the chlorides, bromides, iodides, and methanesulphonates are particularly preferred.

Other preferred anticholinergics are selected from among the salts of formula AC-1

wherein X⁻ denotes an anion with a single negative charge, preferably an anion selected from among the fluoride, chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate and p-toluenesulphonate, preferably an anion with a single negative charge, particularly preferably an anion selected from among the fluoride, chloride, bromide, methanesulphonate and p-toluenesulphonate, particularly preferably bromide, optionally in the form of the racemates, enantiomers or hydrates thereof. Of particular importance are those pharmaceutical combinations which contain the enantiomers of formula AC-1-en

wherein X⁻ may have the above-mentioned meanings. Other preferred anticholinergics are selected from the salts of formula AC-2

wherein R denotes either methyl or ethyl and wherein X⁻ may have the above-mentioned meanings. In an alternativen embodiment the compound of formula AC-2 may also be present in the form of the free base AC-2-base.

Other specified compounds are:

-   tropenol 2,2-diphenylpropionate methobromide, -   scopine 2,2-diphenylpropionate methobromide, -   scopine 2-fluoro-2,2-diphenylacetate methobromide, -   tropenol 2-fluoro-2,2-diphenylacetate methobromide; -   tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide, -   scopine 3,3′,4,4′-tetrafluorobenzilate methobromide, -   tropenol 4,4′-difluorobenzilate methobromide, -   scopine 4,4′-difluorobenzilate methobromide, -   tropenol 3,3′-difluorobenzilate methobromide, -   scopine 3,3′-difluorobenzilate methobromide; -   tropenol 9-hydroxy-fluorene-9-carboxylate methobromide; -   tropenol 9-fluoro-fluorene-9-carboxylate methobromide; -   scopine 9-hydroxy-fluorene-9-carboxylate methobromide; -   scopine 9-fluoro-fluorene-9-carboxylate methobromide; -   tropenol 9-methyl-fluorene-9-carboxylate methobromide; -   scopine 9-methyl-fluorene-9-carboxylate methobromide; -   cyclopropyltropine benzilate methobromide; -   cyclopropyltropine 2,2-diphenylpropionate methobromide; -   cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide; -   cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide; -   cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide; -   cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide; -   cyclopropyltropine methyl 4,4′-difluorobenzilate methobromide. -   tropenol 9-hydroxy-xanthene-9-carboxylate methobromide; -   scopine 9-hydroxy-xanthene-9-carboxylate methobromide; -   tropenol 9-methyl-xanthene-9-carboxylate-methobromide; -   scopine 9-methyl-xanthene-9-carboxylate-methobromide; -   tropenol 9-ethyl-xanthene-9-carboxylate methobromide; -   tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide; -   scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide,

The above-mentioned compounds may also be used as salts within the scope of the present invention, wherein instead of the methobromide the salts metho-X are used, wherein X may have the meanings given hereinbefore for X.

As corticosteroids it is preferable to use compounds selected from among beclomethasone, betamethasone, budesonide, butixocort, ciclesonide, deflazacort, dexamethasone, etiprednol, flunisolide, fluticasone, loteprednol, mometasone, prednisolone, prednisone, rofleponide, triamcinolone, RPR-106541, NS-126, ST-26, and

-   (S)-fluoromethyl     6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate -   (S)-(2-oxo-tetrahydro-furan-3S-yl)6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, -   cyanomethyl     6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-(2,2,3,3-tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17β-carboxylate     optionally in the form of the racemates, enantiomers or     diastereomers thereof and optionally in the form of the salts and     derivatives thereof, the solvates and/or hydrates thereof. Any     reference to steroids includes a reference to any salts or     derivatives, hydrates or solvates thereof which may exist. Examples     of possible salts and derivatives of the steroids may be: alkali     metal salts, such as for example sodium or potassium salts,     sulphobenzoates, phosphates, isonicotinates, acetates,     dichloroacetates, propionates, dihydrogen phosphates, palmitates,     pivalates, or furoates.

PDE4-inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4418, Bay-198004, BY343, CP-325.366, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, and

-   N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide -   (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide -   (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone -   3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-5-methyl-isothioureido]benzyl)-2-pyrrolidone -   cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic     acid] -   2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)cyclohexan-1-one -   cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol] -   (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate -   (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate -   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3.4-c]-1,2,4-triazolo[4.3-a]pyridine -   9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3.4-c]-1,2,4-triazolo[4.3-a]pyridine     optionally in the form of the racemates, enantiomers or     diastereomers thereof and optionally in the form of the     pharmacologically acceptable acid addition salts thereof, the     solvates and/or hydrates thereof. According to the invention the     acid addition salts of the PDE4 inhibitors are preferably selected     from among the hydrochloride, hydrobromide, hydriodide,     hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,     hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,     hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and     hydro-p-toluenesulphonate.

The LTD4-antagonists used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321 and

-   1-((((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic     acid, -   1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropaneacetic     acid -   [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic     acid     optionally in the form of the racemates, enantiomers or     diastereomers thereof and optionally in the form of the     pharmacologically acceptable acid addition salts, solvates and/or     hydrates thereof. According to the invention these acid addition     salts are preferably selected from among the hydrochloride,     hydrobromide, hydroiodide, hydrosulphate, hydrophosphate,     hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate,     hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate,     hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulphonate. By     salts or derivatives which the LTD4-antagonists may optionally be     capable of forming are meant, for example: alkali metal salts, such     as for example sodium or potassium salts, alkaline earth metal     salts, sulphobenzoates, phosphates, isonicotinates, acetates,     propionates, dihydrogen phosphates, palmitates, pivalates, or     furoates.

EGFR-inhibitors which may be used are preferably compounds selected from among cetuximab, trastuzumab, ABX-EGF, Mab ICR-62, and

-   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]-amino}-7-cyclopropylmethoxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)-oxy]-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4(R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)uethoxy]-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6.7-bis-(2-methoxy-ethoxy)-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinyl-carbonyl)amino]-quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine -   3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline -   4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline -   4-[(R)-(1-phenyl-ethyl)amino]-6-{[4(R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline -   4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-{[4-(5.5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yl-oxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethansulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline -   4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2.2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline -   4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline     optionally in the form of the racemates, enantiomers, diastereomers     thereof and optionally in the form of the pharmacologically     acceptable acid addition salts, solvates or hydrates thereof.     According to the invention these acid addition salts are preferably     selected from among the hydrochloride, hydrobromide, hydriodide,     hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate,     hydromaleate, hydroacetate, hydrocitrate, hydrofumarate,     hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and     hydro-p-toluenesulphonate.

The dopamine agonists used are preferably compounds selected from among bromocriptin, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulphonate.

H1-Antihistamines which may be used are preferably compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine, and meclozine, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates, or hydrates thereof. According to the invention these acid addition salts are preferably selected from among the hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate, and hydro-p-toluenesulphonate.

It is also possible to use inhalable macromolecules, as disclosed in EP 1 003 478.

In addition, the compounds may come from the groups of ergot alkaloid derivatives, the triptans, the CGRP-inhibitors, the phosphodiesterase-V inhibitors, optionally in the form of the racemates, enantiomers, or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates, and/or hydrates thereof.

Examples of ergot alkaloid derivatives are dihydroergotamine and ergotamine.

For inhalation, suitable substances include pharmaceutical compositions, pharmaceutical formulations and mixtures with the above-mentioned active substances, as well as the salts and esters thereof and combinations of these active substances, salts, and esters.

The pharmaceutical preparation may additionally contain standard commercial suspension adjuvants, surfactants and/or stabilisers. 

1-10. (canceled)
 11. Device for providing pharmaceutical active substances, active substance mixtures and formulations comprising a container filled with a pharmaceutical preparation, containing an active substance, an active substance mixture or formulation in pressure-liquefied 1.1.1.2-tetrafluoroethane (HFC-134a) or 1.1.1.2.3.3.3-heptafluoropropane(HFC-227) or a mixture of HFC-134a and HFC-227 and comprising a mouthpiece tube consisting of a shaft, a valve stem receptacle, a nozzle bore, wherein the valve stem receptacle has a channel which the nozzle bore impacts upon at an obtuse angle to its perpendicular axis, as a result of which the pharmaceutical composition, mixture or formulation which is liquefied under pressure is deflected through >90° from the perpendicularly downwardly arranged opening of the valve stem and passes outwards through the nozzle bore, thereby generating the spray cloud at the transition from the nozzle bore to the nozzle opening, wherein the diameter of the channel opening in the valve stem receptacle corresponds approximately to the internal diameter of the valve stem and wherein the valve stem has an internal diameter between 1.68 mm to 2.12 mm and wherein the nozzle bore is located at the end of the channel and the channel is tapered towards the nozzle bore such that the width of the channel at the end of the channel is constricted approximately to the diameter of the nozzle bore and wherein the nozzle bore has a diameter of 0.2-0.6 mm.
 12. Device according to claim 11, characterised in that the diameter of the channel opening in the valve stem receptacle (5) corresponds approximately to the internal diameter of the valve stem (4).
 13. Device according to claim 11, characterised in that the pharmaceutical preparation additionally contains suspension adjuvants, surfactants and/or stabilisers.
 14. Device according to claim 11, characterised in that the channel (8) is connected, via the nozzle bore (9), to the nozzle opening (10) which is of funnel-shaped construction.
 15. Device according to claim 12, characterised in that the channel (8) is connected, via the nozzle bore (9), to the nozzle opening (10) which is of funnel-shaped construction.
 16. Device according to claim 11 wherein the pharmaceutical preparation contains an anticholinergic or a betamimetic or a steroid or a phosphodiesterase-IV-inhibitor or a LTD4-antagonist and EGFR-kinase inhibitor or a antiallergic agent or a ergot alkaloid derivative or triptan or a CGRP-antagonist or a phosphodiesterase-V-inhibitor, or combinations of such active substances. 